Formulations for oral delivery of adsorbents in the gut

Abstract

The invention relates to a formulation for the delayed and controlled delivery of an adsorbent into the lower intestine of mammals. The formulation includes a carrageenan and an adsorbent, such as activated charcoal. The invention further relates to uses of this formulation, in particular to pharmaceutical uses. In one embodiment, the formulation is used to eliminate or reduce the side effects in the intestine, in particular in the colon, of pharmaceutical agents that are administered as a treatment for a disorder, but that have side effects when they reach the late ileum, the caecum or the colon.

The invention claimed is: 
     
       1. A formulation comprising:
 a) a substantially water-free core comprising a pellet of activated charcoal mixed with kappa-carrageenan, wherein the amount of kappa-carrageenan is between 5% and 25% by weight of the mixture of the activated charcoal with the kappa-carrageenan and wherein the amount of activated charcoal is between 75%-95% by weight of the mixture of the activated charcoal with the kappa-carrageenan, and 
 b) a layer of an external coating formed around the core, wherein the external coating is a pH-dependent enterosoluble polymer selected from the group consisting of cellulose acetate trimellitate (CAT); cellulose acetate phthalate (CAP); anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid; hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose acetate succinate (HPMCAS); methacrylic acid and ethyl acrylate copolymers; methacrylic acid and methyl methacrylate copolymers (in a 1:1 ratio); methacrylic acid and methyl methacrylate copolymers (in a 1:2 ratio); polyvinyl acetate phthalate (PVAP); and shellac resins, 
 wherein the pH-dependent enterosoluble polymer dissolves at a pH equal to 6.0 and above. 
 
     
     
       2. The formulation of  claim 1 , wherein the amount of kappa-carrageenan is about 15% by weight of the mixture of the activated charcoal with the kappa-carrageenan. 
     
     
       3. The formulation of  claim 1 , wherein the pH-dependent enterosoluble polymer is selected from the group consisting of shellac; hydroxypropylmethylcellulose acetate succinate; hydroxypropylmethylcellulose phthalate; anionic copolymers based on methyl acrylate, methyl methacrylate and methacrylic acid; and methacrylic acid and methyl methacrylate copolymers (in a 1:2 ratio). 
     
     
       4. The formulation of  claim 1 , wherein the external coating is a mixture of (i) an anionic copolymer based on methyl acrylate, methyl methacrylate, and methacrylic acid, and (ii) a copolymer of methacrylic acid and ethyl acrylate, in a (i):(ii) weight ratio between 99:1 and 80:20. 
     
     
       5. The formulation of  claim 1 , wherein a further coating is provided between the core and the external pH-dependent layer, and wherein said further coating is selected from the group consisting of pH-dependent polymers, pH-independent water soluble polymers, pH-independent water insoluble polymers, and mixtures of a pH-dependent polymer and a water insoluble, pH-independent polymer. 
     
     
       6. The formulation of  claim 5 , wherein the pH-dependent polymer is selected from the group consisting of shellac polymers, anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid, methacrylic acid and ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), and hydroxypropylmethylcellulose acetate succinate (HPMCAS). 
     
     
       7. The formulation of  claim 5 , wherein the pH-independent water soluble polymer is selected from the group consisting of polyvinyl pyrrolidone (PVP) and high molecular weight cellulose polymers. 
     
     
       8. The formulation of  claim 7 , wherein the high molecular weight cellulose polymers are selected from the group consisting of hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC). 
     
     
       9. The formulation of  claim 5 , wherein the pH-independent water insoluble polymers are selected from the group consisting of ethylcellulose polymers and copolymers of ethyl acrylate and methyl methacrylate. 
     
     
       10. The formulation of  claim 5  wherein the mixtures of the pH-dependent polymer and the water insoluble, pH-independent polymer comprises a copolymer of ethylcellulose and ethyl acrylate methyl methacrylate. 
     
     
       11. The formulation according to  claim 5 , wherein the further coating comprises at least one cellulose derivative selected from the group consisting of hydroxypropylcellulose and ethylcellulose. 
     
     
       12. The formulation according to  claim 5 , wherein the further coating is made of a 1:9 to 9:1 weight ratio mixture of a methacrylic acid and ethyl acrylate copolymer and an ethyl acrylate and methyl methacrylate copolymer. 
     
     
       13. The formulation of  claim 1 , wherein the enterosoluble polymer layer is from 10% to 40% by weight of the total formulation. 
     
     
       14. The formulation of  claim 1 , wherein and the enterosoluble polymer layer is from 10% to 40% by weight of the total formulation. 
     
     
       15. The formulation of  claim 1 , wherein the pH-dependent enterosoluble polymer is an anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid. 
     
     
       16. The formulation of  claim 1 , wherein the activated charcoal is USP grade activated charcoal. 
     
     
       17. The formulation of  claim 1 , wherein the activated charcoal has a surface area above 1500 m 2 /g. 
     
     
       18. A formulation comprising:
 a) a core comprising activated charcoal mixed with kappa-carrageenan, wherein the amount of kappa-carrageenan is between 15% and 25% by weight of the mixture of the activated charcoal with the kappa-carrageenan and wherein the amount of activated charcoal is between 75%-85% by weight of the mixture of the activated charcoal with the kappa-carrageenan, and 
 b) a layer of an external coating formed around the core, wherein the external coating is a pH-dependent enterosoluble polymer selected from the group consisting of cellulose acetate trimellitate (CAT); cellulose acetate phthalate (CAP); anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid; hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose acetate succinate (HPMCAS); methacrylic acid and ethyl acrylate copolymers; methacrylic acid and methyl methacrylate copolymers (in a 1:1 ratio); methacrylic acid and methyl methacrylate copolymers (in a 1:2 ratio); polyvinyl acetate phthalate (PVAP); and shellac resins, 
 wherein the pH-dependent enterosoluble polymer dissolves at a pH equal to 6.0 and above. 
 
     
     
       19. A formulation comprising:
 a) a core comprising a pellet of activated charcoal mixed with kappa-carrageenan, wherein the amount of kappa-carrageenan is between 5% and 25% by weight of the mixture of the activated charcoal with the kappa-carrageenan and wherein the amount of activated charcoal is between 75%-95% by weight of the mixture of the activated charcoal with the kappa-carrageenan, and 
 b) a layer of an external coating formed around the core, wherein the external coating is a pH-dependent enterosoluble polymer selected from the group consisting of cellulose acetate trimellitate (CAT); cellulose acetate phthalate (CAP); anionic copolymers based on methylacrylate, methylmethacrylate and methacrylic acid; hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose acetate succinate (HPMCAS); methacrylic acid and ethyl acrylate copolymers; methacrylic acid and methyl methacrylate copolymers (in a 1:1 ratio); methacrylic acid and methyl methacrylate copolymers (in a 1:2 ratio); polyvinyl acetate phthalate (PVAP); and shellac resins, 
 wherein the pH-dependent enterosoluble polymer dissolves at a pH equal to 6.0 and above.